The serotonin theory of depression: a systematic review of the evidence (2022)

Important to note that the serotonin theory of depression doesn't have to be strictly true for SSRIs to be effective. People who having passing familiarity with neuroscience often assume that psychiatric medications work by correcting deficiencies, but this isn't true. It's also not accurate to say that SSRIs "give you more serotonin" or any of the other variations on that theme.

Neurotransmitters aren't simple levels in the brain that go up and down, despite how much podcasters and fitness influencers talk about them like that. Neurotransmitter dynamics are complex and the long-term adaptations after taking medications like an SSRI can't be simply described in terms of "levels" going up and down. There are changes in frequency, duration, and movement of Serotonin across synapses that are much more complex. There are also adaptations to the receptors, including auto-receptors which modulate release of neurotransmitters (side note: some newer antidepressants also directly target those autoreceptors with possibly slight improvements in side effect profile).

So keep that in mind when reading anything about the serotonin theory of depression. This is often brought up as a strawman argument to attack SSRIs, but we've known for decades that the serotonin theory of depression never fully explained the situation. We've also known that some conditions like anxiety disorders are associated with increased serotonin activity in parts of the brain, which SSRIs can normalize.

Exactly this - SSRI's efficacy was established based on improvements in reports from depressed people and we formed a theory about the mechanism based on the interactions we understood. As we try to prove that theory out it turns out our theories don't hold - but people who are depressed still improve when on SSRIs! So we're still working on the mechanism (which we always knew was incomplete at best) but this work isn't about the underlying efficacy of the drugs on the condition. It's about the nerdy explanation for why SSRIs work.

SSRIs aren’t shown to be much better than placebo and are shown to be about as effective as therapy — which is actually durable.

There’s also rates of sexual side effects in excess of 70% [1] and they cause weight gain which is separately associated with depression.

In fact industry data shows a smaller gap between SSRIs and placebo than FDA data. See Figure 1. [2]

The problem with SSRIs is that serotonin receptors are all over the body including in the gonads and they play a large role in appetite regulation.

They do something but it’s not nearly what people assume.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/

> The problem with SSRIs [...]

Yah, serotonin is involved in a lot! I don't think that's a problem? You aren't saying it directly, but I feel like you are pointing to SSRI side effects as if they invalidate that SSRIs help depression. That's not true! People can choose if they want therapy or SSRIs or both. If your doctor has been telling you serotonin dis-regulation directly causes depression that's probably wrong - but if they tell you that SSRIs help many depressed people that's right.

I'm pointing at it as a problem because that's what causes the e.g. sexual side effects. It's why you don't get them from, e.g. bupropion (an NDRI and nicotinic receptor antagonist) that act on the noradrenergic, dopaminergic and nicotinic systems - and not on seratonergic.

Regarding helping people with depression, the numbers don't really support a strong effect especially against an active placebo that makes you feel different like atropine.

[edit] Don't misunderstand, I'm not saying that there's not a role for pharmaceuticals. Just that the data for SSRIs specifically is not nearly as compelling as the quantity of prescriptions for it would have you believe, and they probably shouldn't be front-line treatment.